Indole derivatives with 5HT6 receptor affinity

Abstract

This invention relates to compounds which have generally 5-HT6 receptor affinity and which are represented by Formula I:wherein one of R<5>, R<6 >or R<7 >is a group of general Formula B, wherein W is a -CH- group or a nitrogen atom, and the other substituents are as defined herein; or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof. The invention further relates to pharmaceutical compositions containing such compounds, methods for their use as therapeutic agents, and methods of preparation thereof.

What is claimed is:  
     
       1. A compound of Formula I:                    
       wherein: 
       R 1  is —S(O) 0-2 —A, —C(O)—A, or —(CH 2 ) 0-1 —A, wherein A is selected from aryl and heteroaryl, said heteroaryl being a monovalent aromatic carbocyclic radical having one or two rings incorporating one, two, or three heteroatoms chosen from nitrogen, oxygen, or sulfur, and said aryl and heteroaryl are each independently in each occurrence optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino;  
       R 2  is selected from hydrogen, C 1-6 -alkyl, C 1-6 -alkoxy, and C 1-6 -alkylthio;  
       R 3  is selected from hydrogen and C 1-6 -alkyl;  
       R 4  is selected from hydrogen, halogen, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkylthio, halo-C 1-6 -alkyl, cyano, and C 1-6 -alkylcarbonyl; and  
       one of R 5 , R 6  or R 7  is a group of general Formula B, wherein W is or a nitrogen atom, and R 8 , R 9  and R 10  are each independently selected from hydrogen, C 1-10 -alkyl and benzyl;                    
       and the others are each independently of each other selected from hydrogen, halogen, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkylthio, haloalkyl, cyano, and C 1-6 -alkylcarbonyl;  
       or individual isomers, racemic or non racemic mixtures of isomers, prodrugs, or pharmaceutically acceptable salts or solvates thereof. 
     
     
       2. The compound of  claim 1 , wherein R 1  is —SO 2 —A. 
     
     
       3. The compound of  claim 2 , wherein A is an aryl group. 
     
     
       4. The compound of  claim 2 , wherein A is phenyl optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino. 
     
     
       5. The compound of  claim 1 , wherein R 1  is —S—A. 
     
     
       6. The compound of  claim 5 , wherein A is an aryl group. 
     
     
       7. The compound of  claim 5 , wherein A is phenyl optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino. 
     
     
       8. A compound of Formula I comprising:                    
       wherein: 
       R 1  is —SO 0-2 —A, —C(O)—A, or —(CH 2 ) 0-1 —A, wherein A is aryl or heteroaryl, said heteroaryl being monovalent aromatic carbocyclic radical having one or two rings incorporating one, two, or three heteroatoms chosen from nitrogen, oxygen, or sulfur; said aryl and heteroaryl are each independently in each occurrence optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino;  
       R 2  is selected from hydrogen, C 1-6 -alkyl, C 1-6 -alkoxy, and C 1-6 -alkylthio;  
       R 3  is selected from hydrogen and C 1-6 -alkyl;  
       R 7  is a group of general Formula B, wherein W is a nitrogen atom, and R 8 , R 9  and  
       R 10  are each independently selected from hydrogen and C 1 -C 10 -alkyl;                    
       and R 4 , R 5  and R 6  are each independently of each other selected from hydrogen, halogen, C 1-6 -alkyl, C 1-6 -alkylthio, halo-C 1-6 -alkyl, cyano, and C 1-6 -alkylcarbonyl; 
       or individual isomers, racemic or non racemic mixtures of isomers, prodrugs, or pharmaceutically acceptable salts or solvates thereof. 
     
     
       9. The compound of  claim 8 , wherein R 1  is —SO 2 —A. 
     
     
       10. The compound of  claim 9 , wherein A is aryl, optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino. 
     
     
       11. The compound of  claim 9 , wherein A is phenyl optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino. 
     
     
       12. The compound of  claim 9 , wherein A is heteroaryl, said heteroaryl being a monovalent aromatic carbocyclic radical having one or two rings incorporating one, two, or three heteroatoms chosen from nitrogen, oxygen, or sulfur, said heteroaryl optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino. 
     
     
       13. The compound of  claim 9 , wherein A is pyridinyl or benzothiazolyl, said pyridinyl or benzothiazolyl being each independently of each other optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino. 
     
     
       14. The compound of  claim 8 , wherein R 1  is —S—A. 
     
     
       15. The compound of  claim 14 , wherein A is aryl, optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino. 
     
     
       16. The compound of  claim 14 , wherein A is phenyl optionally substituted with one or more optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino. 
     
     
       17. A compound of Formula I comprising:                    
       wherein: 
       R 1  is —S(O) 0-2 —A, —C(O)—A, or —(CH 2 ) 0-1 —A, wherein A is aryl or heteroaryl, said heteroaryl being a monovalent aromatic carbocyclic radical having one or two rings incorporating one, two, or three heteroatoms chosen from nitrogen, oxygen, or sulfur; and said aryl and heteroaryl are each independently of each other in each occurrence optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino;  
       R 2  is selected from hydrogen, C 1-6 -alkyl, C 1-6 -alkoxy, and C 1-6 -alkylthio;  
       R 3  is selected from hydrogen and C 1-6 -alkyl;  
       R 5  is a group of general formula B, wherein W is a nitrogen atom, and R 8 , R 9  and R 10  are each independently selected from hydrogen and C 1-10 -alkyl;                    
       and R 4 , R 6  and R 7  are each independently of each other selected from hydrogen, halogen, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkylthio, halo-C 1-6 -alkyl, cyano, and alkylcarbonyl;  
       or individual isomers, racemic or non racemic mixtures of isomers, prodrugs, or pharmaceutically acceptable salts or solvates thereof. 
     
     
       18. The compound of  claim 17 , wherein R 1  is —SO 2 —A. 
     
     
       19. The compound of  claim 18 , wherein A is aryl. 
     
     
       20. The compound of  claim 18 , wherein A is phenyl optionally substituted with one or more optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino. 
     
     
       21. The compound of  claim 17 , wherein R 1  is —S—A. 
     
     
       22. The compound of  claim 21 , wherein A is aryl, optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino. 
     
     
       23. The compound of  claim 21 , wherein A is phenyl optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino. 
     
     
       24. The compound of  claim 8 , wherein the compound is: 
       3-benzenesulfonyl-7-piperazin-1-yl-1H-indole;  
       3-benzenesulfonyl-1-methyl-7-piperazin-1-yl-1H-indole;  
       3-benzenesulfonyl-2-methyl-7-piperazin-1-yl-1H-indole;  
       3-(4-chlorobenzenesulfonyl)-2-methyl-7-piperazin-1-yl-1H-indole;  
       3-(4-methoxybenzenesulfonyl)-2-methyl-7-piperazin-1-yl-1H-indole;  
       7-piperazin-1-yl-3-(pyridine-4-sulfonyl)-1H-indole;  
       7-piperazin-1-yl-3-(pyridine-2-sulfonyl)-1H-indole;  
       1-methyl-7-piperazin-1-yl-3-(pyridine-2-sulfonyl)-1H-indole;  
       3-benzenesulfonyl-7-(4-methyl-piperazin-1-yl)-1H-indole;  
       3-(3,4-dichloro-benzenesulfonyl)-7-piperazin-1-yl-1H-indole;  
       2-(7-piperazin-1-yl-1H-indole-3-sulfonyl)-benzothiazole;  
       3-(4-fluoro-benzenesulfonyl)-2-methyl-7-piperazin-1-yl-1H-indole;  
       3-(4-fluoro-benzenesulfonyl)-7-piperazin-1-yl-1H-indole;  
       7-piperazin-1-yl-3-(toluene-4-sulfonyl)-1H-indole;  
       3-(3,5-dichloro-benzenesulfonyl)-7-piperazin-1-yl-1H-indole;  
       3-(3-chloro-benzenesulfonyl)-7-piperazin-1-yl-1H-indole;  
       3-(2-chloro-benzenesulfonyl)-7-piperazin-1-yl-1H-indole;  
       7-piperazin-1-yl-3-(2-trifluoromethyl-benzenesulfonyl)-1H-indole;  
       1-methyl-7-piperazin-1-yl-3-(2-trifluoromethyl-benzenesulfonyl)-1H-indole;  
       3-(4-fluoro-benzenesulfonyl)-1-methyl-7-piperazin-1-yl-1H-indole;  
       1-methyl-7-piperazin-1-yl-3-(pyridine-2-sulfonyl)-1H-indole;  
       1-methyl-7-piperazin-1-yl-3-(3-trifluoromethyl-benzenesulfonyl)-1H-indole;  
       3-(2-chloro-benzenesulfonyl)-1-methyl-7-piperazin-1-yl-1H-indole;  
       3-(3-chloro-benzenesulfonyl)-1-methyl-7-piperazin-1-yl-1H-indole;  
       3-benzenesulfonyl-1-methyl-7-(4-methyl-piperazin-1-yl)-1H-indole;  
       3-(3,4-dichloro-benzenesulfonyl)-7-(4-methyl-piperazin-1-yl)-1H-indole;  
       3-(2-chloro-benzenesulfonyl)-7-(4-methyl-piperazin-1-yl)-1H-indole;  
       3-(3-chloro-benzenesulfonyl)-7-(4-methyl-piperazin-1-yl)-1H-indole;  
       3-(2,4-dichloro-benzenesulfonyl)-7-(4-methyl-piperazin-1-yl)-1H-indole;  
       3-(3,5-dichloro-benzenesulfonyl)-7-(4-methyl-piperazin-1-yl)-1H-indole;  
       7-(4-methyl-piperazin-1-yl)-3-(2-trifluoromethyl-benzenesulfonyl)-1H-indole;  
       3-phenylsulfanyl-7-piperazin-1-yl-1H-indole;  
       or an individual isomer, racemic or non-racemic mixture of isomers, or pharmaceutically acceptable salt or solvate thereof. 
     
     
       25. The compound of  claim 17 , wherein the compound is: 
       3-benzenesulfonyl-5-piperazin-1-yl-1H-indole;  
       3-benzenesulfonyl-1-methyl-5-piperazin-1-yl-1H-indole;  
       3-(2,3-dichloro-phenylsulfanyl)-5-piperazin-1-yl-1H-indole;  
       3-(2,3-dichloro-benzenesulfonyl)-5-piperazin-1-yl-1H-indole;  
       3-(2,3-dichloro-benzenesulfonyl)-1-methyl-5-piperazin-1-yl-1H-indole;  
       1-methyl-5-piperazin-1-yl-3-(3-trifluoromethyl-benzenesulfonyl)-1H-indole;  
       5-piperazin-1-yl-3-(4-trifluoromethyl-benzenesulfonyl)-1H-indole;  
       3-(4-chloro-benzenesulfonyl)-5-piperazin-1-yl-1H-indole;  
       3-(3,5-dichloro-benzenesulfonyl)-5-piperazin-1-yl-1H-indole;  
       3-(3,5-dichloro-benzenesulfonyl)-1-methyl-5-piperazin-1-yl-1H-indole;  
       3-phenylsullfanyl-5-piperazin-1-yl-1H-indole;  
       3-(2-chloro-benzenesulfonyl)-5-piperazin-1-yl-1H-indole;  
       3-(4-fluoro-benzenesulfonyl)-5-piperazin-1-yl-1H-indole;  
       3-(4-fluoro-benzenesulfonyl)-1-methyl-5-piperazin-1-yl-1H-indole;  
       3-(2-chloro-benzenesulfonyl)-1-methyl-5-piperazin-1-yl-1H-indole;  
       or an individual isomer, racemic or non-racemic mixture of isomers, or pharmaceutically acceptable salt or solvate thereof. 
     
     
       26. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of  claim 1  in admixture with at least one pharmaceutically acceptable carrier. 
     
     
       27. A process for preparing a compound as claimed in  claim 1 , said process comprising 
       i) reacting a compound having a general Formula 4                   
        wherein P is a protecting group and R 2 , R 4 , R 9  and R 10  are as defined in  claim 1 , with a compound of general formula (A—S) 2 , wherein A is aryl or heteroaryl' 
       ii) optional alkylation of the nitrogen of the indole group,  
       iii) removal of the protecting group P;  
       to provide a compound of Formula I,                    
        wherein R 8  is hydrogen, and A, R 2 , R 3 , R 4 , R 9 , and R 10  are as defined in  claim 1 , and  
       iv) optional alkylation to provide a compound of the general Formula I, wherein R 8  is C 1-10 -alkyl, and A, R 2 , R 3 , R 4 , R 9 , and R 10  are as defined in  claim 1 .  
     
     
       28. A process for preparing a compound as claimed in  claim 1  which comprises 
       i) reacting a compound having a general Formula 4                   
        wherein P is a protecting group and R 2 , R 4 , R 9  and R 10  are as defined in  claim 1  with a compound of general formula (A—S) 2 , wherein A is aryl or heteroaryl, to provide an adduct 4a                    
       ii) oxidation of the sulfur atom of 4a;  
       iii) optional alkylation of the nitrogen of the indole group of oxidized 4a;  
       iv) removal of the protecting group P;  
       to provide a compound of Formula I,                    
        wherein R 8  is hydrogen, and A, R 2 , R 3 , R 4 , R 9 , and R 10  are as defined in  claim 1 , and  
       v) optional alkylation of the nitrogen of the piperazine or piperidine group to provide a compound of the general Formula I, wherein R 8  is C 1-10 -alkyl, and A, R 2 , R 3 , R 4 , R 9 , and R 10  are as defined in  claim 1 .  
     
     
       29. A process for preparing a compound as claimed in  claim 1 , said process comprising 
       i) reacting 1-halo-2-nitrobenzene with a halomethanesulfonyl benzene to provide a 1-benzenesulfonylmethyl-2-nitrobenzene  
       ii) amination of the 1-benzenesulfonylmethyl-2-nitrobenzene with a 1-alkylpiperazine to provide a piperazinylated nitrobenzene;  
       iii) reduction of the nitro group of the piperazinylated nitrobenzene, and  
       iv) addition of an orthoformate, followed by cyclization to yield a compound of Formula 18a,                    
       wherein R 8  is C 1-10 -alkyl and A, R 9 , and R 10  are as defined in the summary of the invention.  
     
     
       30. A process for preparing a compound of  claim 1 , said process comprising 
       i) reacting a compound having a general Formula 4                   
        wherein P is a protecting group and R 2 , R 4 , R 9  and R 10  are as defined in  claim 1  with a compound of general formula (A—S) 2 , wherein A is aryl or heteroaryl, to provide an adduct 4a                    
       ii) oxidation of the sulfur atom of 4a;  
       iii) optional alkylation of the nitrogen of the indole group of oxidized 4a;  
       iv) removal of the protecting group P;  
       to provide a compound of Formula I,                    
        wherein R 8  is hydrogen, and A, R 2 , R 3 , R 4 , R 9 , and R 10  are as defined as  claim 1 , and  
       v) optional alkylation of the nitrogen of the piperazine or piperidine group to provide a compound of the general Formula I, wherein R 8  is C 1-10 -alkyl, and A, R 2 , R 3 , R 4 , R 9 , and R 10  are as defined in  claim 1 .  
     
     
       31. A method of treating a subject that has a disease state selected from schizophrenia, depression, memory disorders, attention deficit disorder, and Alzheimer's disease wherein said method comprises administering to said subject a therapeutically effective amount of the compound of  claim 1 . 
     
     
       32. A method for treating a subject that has a disorders of the gastrointestinal tract, said method comprising administering to said subject a therapeutically effective amount of the compound of  claim 1 .